Response to Subsequent Novel Therapies and Time to Second Progression-Free Survival Event in the MURANO Trial in Patients with R/R CLL Previously Treated with Fixed-Dose Venetoclax/Rituximab

The randomized phase 3 MURANO trial (NCT02005471) evaluated fixed-duration venetoclax/rituximab treatment in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). To better understand the efficacy of subsequent treatment after relapse, the current final analysis of the MURANO trial assessed response to subsequent therapy with venetoclax-based regimens or Bruton tyrosine kinase inhibitor (BTKi) therapy, as well as time to the second progression-free survival (PFS) events.

A total of 389 patients with R/R CLL were randomized to receive venetoclax/rituximab (2 years of venetoclax, in combination with rituximab for the first 6 months) or 6 months of bendamustine/rituximab. Patients with progressive disease (PD) were followed for disease response to any subsequent anti-CLL therapeutic regimens, PFS, and overall survival (OS). A sub-study permitted patients who developed progressive disease (PD) following treatment with venetoclax/rituximab or bendamustine/rituximab to receive the MURANO venetoclax/rituximab regimen. Date of final clinical cutoff was August 3, 2022.

At the cutoff date, of the 194 patients in the venetoclax/rituximab arm, 73 (37.6%) had not received a next-line therapy, and 26 patients had died without subsequent therapy. In the bendamustine/rituximab arm, 36 patients (18.5%) had not received next-line therapy and 28 patients had died without subsequent therapy. Following PD, 95 (49.0%) patients in the venetoclax/rituximab arm and 131 (67.2%) patients in the bendamustine/rituximab arm had received subsequent anti-CLL therapy.

Of the 95 patients in the venetoclax/rituximab arm who received subsequent anti-CLL therapy, 32.3% received BTKi therapy; 50.5% received venetoclax-based therapy, and 17.2% received chemoimmunotherapy (CIT). Of the 131 patients in the bendamustine/rituximab arm who received subsequent therapy, 60.3% received BTKi therapy, 13.0% received venetoclax-based therapy, 18.3% received CIT; and 8.4% received other novel agents.

The best overall response (BOR; defined as complete remission [CR], CR with incomplete count recovery, partial remission [PR], and nodular PR) rate in the cohort previously treated with venetoclax/rituximab on subsequent venetoclax-based therapy, was 76.2% and the BOR rate for patients previously treated with bendamustine/rituximab on subsequent venetoclax-based therapy was 88.2%. For patients on subsequent BTKi therapy previously treated with venetoclax/rituximab, the BOR rate was 82.6% and 78.5% for patients pretreated with bendamustine/rituximab. Time from randomization to second PFS event was not estimable in the venetoclax/rituximab arm and was 77.8 months in the bendamustine/rituximab arm (hazard ratio [HR], 0.49).

In patients treated with venetoclax/rituximab who received subsequent therapy, median PFS (time zero taken at initiation of next-line therapy) was 42.9 months with subsequent BTKi therapy (n=30), 59.9 months with venetoclax based therapy (n=47), and 12.1 months with subsequent CIT (n=16). Median PFS from initiation of new therapy was 45.3 months for patients randomized to venetoclax/rituximab and 38.2 months for patients treated with bendamustine/rituximab (HR, 0.84); median OS from initiation of new therapy was 70.9 months for patients randomized to venetoclax/rituximab and 67.5 months for patients treated with bendamustine/rituximab (HR, 0.93).

Final data from MURANO demonstrated a significantly prolonged time to second PFS event in the venetoclax/rituximab arm, with high response rates achieved by patients who subsequently received retreatment or crossed over to venetoclax-based regimens or BTKi therapy. Based on these results, it was concluded that “early intervention with fixed-duration venetoclax/rituximab in R/R CLL is an effective approach and does not compromise subsequent therapy response.”

Source:

Harrup R A, Kater A, Eichhorst B, et al. Response to subsequent novel therapies and time to second progression-free survival event in the MURANO trial in patients with relapsed/refractory chronic lymphocytic leukemia previously treated with fixed-dose venetoclax plus rituximab. Presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, December 9-12, 2023; San Diego, CA: Poster 1898.